RNA interference (RNAi) provides a means to silence the expression of a target gene. It provides basic research with a method for studying genetic and biochemical pathways, and the function of individual genes and gene products. Consequently, RNAi has become a critical tool for target validation in the pharmaceutical industry, and substantial investments have been made with the goal of developing drugs based on RNA complexes capable of mediating RNA interference against genes whose aberrant expression is linked to a disease state or condition.
However, the ability of RNA complexes to function as an RNAi therapeutic is limited by such problems as sequence specificity or “off-target” effect, potency, nuclease stability, and non-specific cytokine induction.
This disclosure provides compounds, compositions, methods and uses for improving RNAi activity of RNA complexes while at the same time minimizing or eliminating the adverse problems associated with RNA complexes in RNAi. Among other things, this application provides novel compounds and compositions for making and using RNA complexes that have improved potency and nuclease stability, and have reduced or eliminated “off-target” effect and/or cytokine induction.